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CN117700479A - Targeted prostate specific membrane antigen inhibitor, radioactive marker, preparation method and application thereof - Google Patents

Targeted prostate specific membrane antigen inhibitor, radioactive marker, preparation method and application thereof Download PDF

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CN117700479A
CN117700479A CN202310495837.7A CN202310495837A CN117700479A CN 117700479 A CN117700479 A CN 117700479A CN 202310495837 A CN202310495837 A CN 202310495837A CN 117700479 A CN117700479 A CN 117700479A
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dmf
acid
psma
reaction
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罗田伟
李洪玉
孙明月
张文辉
高菲
王宁
黄旭虎
邱珊珊
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Atom High Tech Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/02—Linear peptides containing at least one abnormal peptide link
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/0474—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group
    • A61K51/0482—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group chelates from cyclic ligands, e.g. DOTA
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
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    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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Abstract

The invention relates to the technical field of biological medicines, in particular to a targeted prostate specific membrane antigen inhibitor, a radioactive marker, a preparation method and application thereof. The chemical structure of the targeted PSMA inhibitor is shown as formula IThe solid phase synthesis method is adopted for synthesis, and the preparation method is simple, novel in structure and stable in physical and chemical properties. The radionuclide of the radioactive marker has high labeling speed, high labeling rate and high purity, shows good bioactivity, has high tumor uptake and lower kidney uptake, can obviously improve the nuclide treatment and imaging effect of the targeted PSMA, meets clinical requirements, and has important significance for diagnosis and treatment of the prostate cancer and metastasis thereof.

Description

Targeted prostate specific membrane antigen inhibitor, radioactive marker, preparation method and application thereof
Technical Field
The invention relates to the technical field of biological medicines, in particular to a targeted prostate specific membrane antigen inhibitor, a radioactive marker, a preparation method and application thereof.
Background
Prostate cancer (PCa) is one of the most common malignant tumors in men. According to 2020 global cancer burden data issued by world health organization, the incidence rate of the prostate cancer is 2 nd in all malignant tumors of men, the death rate is 5 th, the number of the prostate cancer is 140 ten thousand per year, and the number of the prostate cancer deaths per year is 38 ten thousand per year.
Prostate Specific Membrane Antigen (PSMA) is a type ii transmembrane protein highly expressed in prostate cancer (PCa), and PSMA is highly overexpressed in more than 90% of PCa lesions and related bone and lymph node metastasis lesions, with increased expression levels as the degree of tumor dedifferentiation, metastasis and hormonal resistance increase, but is underexpressed in normal human tissues such as prostate epithelium, small intestine, liver, kidney and salivary glands at levels of only 1% to 1% of prostate cancer.
PSMA is considered to be an ideal target for diagnosis and treatment of prostate cancer, and a ligand targeting PSMA should have high selectivity and be capable of efficiently and specifically binding to PSMA on the surface of prostate cancer cells. Glutamic acid-urea-lysine is taken as a targeting PSMA group, can be combined with PSMA with high efficiency and specificity, has the characteristics of convenience in synthesis and purification, easiness in connection with other molecules, easiness in dissolution in water, stable storage and the like, and is the key point of the research and development of radiopharmaceuticals in recent years. PSMA-11, PSMA-617, PSMA-I & T are representative compounds based on this targeting group.
Although PSMA-targeted ligands have advanced to some extent in the diagnosis and treatment of prostate cancer, there are limitations such as a relatively short biological half-life, high in vivo metabolism rate, low effective dose at tumor sites, too short retention time, and high dose (activity) required to achieve therapeutic effect; in addition, high intake in the kidneys, bones and salivary glands can cause side effects such as nephrotoxicity, bone marrow toxicity and xerostomia to various degrees, and the risk of adverse reactions is increased. Therefore, continuous improvement and optimization of the medicines are needed to improve the pharmacokinetic characteristics of the medicines, enhance the uptake and retention of the medicines at tumor sites, further improve the effectiveness of the medicines and reduce adverse reactions, so that the medicines are suitable for nuclide treatment and imaging of PSMA high-expression tumors, and meet clinical requirements.
Disclosure of Invention
The invention aims to provide a targeted prostate specific membrane antigen inhibitor, a radioactive marker, a preparation method and application thereof, wherein the inhibitor shows good biological activity, has high tumor uptake and lower kidney uptake, and can remarkably improve the treatment and imaging effects of targeted PSMA nuclides so as to meet clinical requirements.
In order to achieve the above object, the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein the structure of the compound is shown as formula (I):
wherein R is 1 Independently selected from one of hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy; the groups adopted by the substitution are halogen.
The compound or a pharmaceutically acceptable salt thereof is mainly used as an inhibitor targeting Prostate Specific Membrane Antigen (PSMA), which is overexpressed on the surface of almost all prostate cancer cells, and further increases in poorly differentiated, metastatic and hormone-resistant prostate cancer cells, and thus, PSMA is an extremely attractive target for diagnosis and treatment of prostate cancer. The invention provides a novel structure for the prostate specific membrane antigen inhibitor, and biological test results show that the uptake and retention of the prostate specific membrane antigen inhibitor in tumors are obviously enhanced, and the treatment and imaging effects of the targeted PSMA nuclide can be improved.
Pharmaceutically acceptable salts include acetic acid (acetic acid) salts, trifluoroacetate, hydrochloride, sodium, potassium, calcium, ammonium, organoamino or magnesium salts, or the like.
Further, R 1 Selected from halogen, C 1 -C 12 Alkyl or C of (2) 1 -C 12 Is one of the alkoxy groups of (a); preferably, R 1 Selected from halogen, C 1 -C 5 Alkyl or C of (2) 1 -C 5 Is one of the alkoxy groups of (a); the halogen is one of chlorine, bromine and iodine; preferably, R 1 Is CH 3 、OCH 3 Or I, the structural formulas are shown as the following I-1, I-2 and I-3:
the compound provided by the invention has a DOTA ligand structure, and the amidation grafted small molecular structure is regulated and controlled to show good biological activity, and has high tumor uptake and lower kidney uptake, so that the treatment and imaging effects of the targeted PSMA nuclide are obviously improved.
Furthermore, the invention also provides a preparation method of the compound, which comprises the following steps:
s1, taking CTC resin as a starting material, adding a compound 1 with a structure shown in the following formula for reaction:
s2, removing Fmoc protecting groups of the compound 1, and then adding Fmoc-3- (3-quinoline) -L-alanine to remove Fmoc; then, the amidation reaction of tranexamic acid, lys (Dde) and DOTA (tris tBu) is carried out by the same method;
s3, removing Dde groups of the Lys (Dde), and adding phenylbutyric acid or para-position substituents thereof to carry out amidation reaction; and then removing the residual protecting groups and the CTC resin to obtain the prostate specific membrane antigen inhibitor.
Further, step S1 includes: the CTC resin and the compound 1 are subjected to air blowing reaction under the action of a catalyst N, N-diisopropylethylamine, and then the resin is washed to obtain the CTC resin grafted with the compound 1;
preferably, the reaction solvent of step S1 is DMF, and the washing comprises: washing with DMF and methanol was performed sequentially.
Further, step S2 includes: removing Fmoc protecting groups of the compound 1 by blowing with a solution of piperidine/DMF, and then washing the CTC resin grafted with the compound 1 with DMF; then Fmoc-3- (3-quinoline) -L-alanine, 2- (7-aza-benzotriazol) -N, N, N ', N' -tetramethyl urea hexafluorophosphate, N-methyl morpholine and DMF are added for air blowing reaction; finally, the amidation reaction of tranexamic acid, lys (Dde) and DOTA (tris tBu) was performed in the same manner.
Further, step S3 includes: adding hydrazine hydrate/DMF solution to remove Dde groups of the Lys (Dde); then adding phenylbutyric acid or para-substituent thereof, 2- (7-aza-benzotriazol) -N, N, N ', N' -tetramethyl urea hexafluorophosphate, N-methyl morpholine and DMF, and washing resin by adopting DMF and methyl tertiary butyl ether in sequence after the air blowing reaction is completed; finally, adding trifluoroacetic acid/water solution, removing the CTC resin, filtering, and purifying the filtrate by adopting tert-butyl methyl ether to obtain the prostate specific membrane antigen inhibitor;
preferably, after the purification of the tert-butyl methyl ether, the tert-butyl methyl ether is pumped out, and after HPLC purification and salt exchange, the freeze-drying is carried out to obtain the white freeze-dried powder of the prostate specific membrane antigen inhibitor.
Preferably, the para-substituent is phenylbutyric acid substituted para-with halogen, alkyl or alkoxy, preferably p-methylbenzoic acid, p-methoxyphenylbutyric acid or p-iodophenylbutyric acid (4- (p-iodophenyl) butyric acid).
As a specific embodiment, the preparation method of the compound shown in the formula (I) comprises the following steps:
in the first step, the reactor was charged with CTC resin (o-chlorophenyl-diphenyl-chloromethane, 1g,0.4 mmol), compound 1 (0.4 mmol,0.26 g), DIPEA (N, N-diisopropylethylamine, 1mmol,0.14 mL) and DMF (dimethylformamide, 8 mL). After the mixture was aerated for 3 hours, it was washed 3 times with DMF and 3 times with methanol to give Compound 2 (1.16 g). The degree of substitution of the resin was calculated based on the weight of the resin (compound 2), and the reaction scale was recalculated to be about 0.25mmol, and the yield of this step was 62.5%.
In the second step, the resin (Compound 2) obtained in step 1 was charged into the reactor and swollen again with DMF (8 mL/g resin, about 9.5 mL) for 2 hours. The Fmoc protecting group was removed by bubbling a 20% solution of piperidine/DMF (in the mixed solution, the volume fraction of piperidine was 20%) for 30 minutes with the addition of three times the volume of the resin bed, and washed 5 times with DMF. To the reactor was charged 2 times (molar amount relative to compound 2) Fmoc-3- (3-quinoline) -L-alanine (0.220 g), 1.9 times (molar amount relative to compound 2) HATU (2- (7-azabenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate, 0.180 g), 4 times (molar amount relative to compound 2) N-methylmorpholine (0.110 mL) and 0.5 times the resin bed volume DMF (about 3 mL), and a small amount of resin was taken for ninhydrin detection to show negative 1 hour of bubbling. The reaction solution was filtered off and washed 3 times with three times the volume of DMF of the resin bed. The above steps of Fmoc removal and amino acid ligation were repeated and tranexamic acid, lys (Dde) and DOTA (tris tBu) (DOTA-tri-tert-butyl-succinimidyl ester) were attached to the resin to give compound 3.
And thirdly, adding a 2% hydrazine hydrate/DMF solution (the volume content of hydrazine hydrate in the mixed solution is 2%) with the volume of the resin bed being three times as large as that of the compound 3, bubbling for 30 minutes, filtering the solution in the reactor, and washing with DMF with the volume of the resin bed being three times as large for 5 times to obtain the compound 4.
In the fourth step, 2 times (relative to the molar amount of Compound 4) of p-tolubutyric acid (0.089 g), 1.9 times (relative to the molar amount of Compound 4) of HATU (0.180 g), 4 times (relative to the molar amount of Compound 4) of N-methylmorpholine (0.110 mL) and 0.5 times of resin bed volume of DMF were charged into the reactor, and the mixture was bubbled with a small amount of resin for 1 hour to perform ninhydrin test, showing a negative. The reaction solution was filtered off, washed 3 times with DMF volume of three times the resin bed volume, and then washed 3 times with methyl tert-butyl ether followed by vacuum drying to give Compound 5 (1.4 g). The yield of step 2-4 was 100%.
In the fifth step, 95% trifluoroacetic acid/water solution (14 mL) was added to the resin (Compound 5), and the mixed solution was stirred for 3 hours at a reaction temperature of 25 ℃. The resin was filtered and tert-butyl methyl ether (112 mL) was added to the filtrate at-20deg.C. The suspension was centrifuged, the supernatant was removed, tert-butyl methyl ether was added, the mixture was stirred to precipitate, and the precipitate was centrifuged again, the supernatant was removed, and the mixture was placed in a constant temperature oven for 16 hours, and tert-butyl methyl ether was drained (crude product 305mg was obtained). Purification by HPLC and salt exchange followed by lyophilization with a lyophilizer gave Ac salt of DOTA-CPN-PSMA as a white lyophilized powder (80 mg, overall yield 24.0%).
The synthetic route of the specific steps is as follows:
the preparation method of the inhibitor with other structures provided by the invention can be used for preparing the inhibitor DOTA-CPN-PSMA (I-1) by referring to the synthetic route of the inhibitor based on the conventional means.
Furthermore, the invention also provides a radioactive marker, which is obtained by using the compound shown in the formula (I) as a ligand and labeling the radionuclide. The structural formula is shown as formula (II):
wherein R is 1 Independently selected from one of hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, wherein the groups employed for the substitution are halogen; m is selected from 68 Ga、 177 Lu、 64 Cu、 225 Ac、 212 Pb、 67 Cu、 161 Tb、 47 Sc or 90 Y.
Further, R 1 Selected from halogen, C 1 -C 12 Alkyl or C of (2) 1 -C 12 Is one of the alkoxy groups of (a); preferably, R 1 Selected from halogen, C 1 -C 5 Alkyl or C of (2) 1 -C 5 Is one of the alkoxy groups of (a); the halogen is one of chlorine, bromine and iodine; preferably, R 1 Is CH 3 、OCH 3 Or I.
Further, the invention also provides a preparation method of the radiolabel, which comprises the following steps: adding the compound into acetic acid-sodium acetate buffer solution, adding radioactive solution containing M, heating for reaction for 5-30 min, cooling after the reaction is finished, diluting with normal saline, and collecting into a sterile vacuum bottle to obtain the radioactive marker.
Furthermore, the invention also provides application of the compound or pharmaceutically acceptable salt thereof or the radiolabel in preparing medicaments for diagnosing or treating the prostate cancer, preferably in preparing medicaments for treating and imaging PSMA high-expression tumors (prostate cancer).
The beneficial effects of the invention are as follows:
the targeted prostate specific membrane antigen inhibitor provided by the invention has the advantages of novel structure and stable physicochemical properties. It can realize rapid labeling with radionuclide, and has high labeling rate and purity. The labeled radiopharmaceuticals have higher lipophilicity, have higher uptake in tumors mainly through renal metabolism, have lower uptake in other non-target organs, have high radioactive clearance speed in non-target areas, and have small nonspecific uptake in glands. The biological distribution experimental result shows that the uptake and retention of the PSMA in tumors are obviously enhanced, the nuclide treatment and imaging effects of the targeted PSMA can be improved, the clinical requirements are met, and the PSMA has important significance for diagnosis and treatment of prostate cancer and metastases thereof.
Drawings
FIG. 1 is an HPLC chromatogram (upper panel) and a mass spectrum (lower panel) of the precursor compound DOTA-CPN-PSMA;
FIG. 2 is a schematic view of 177 HPLC profile of Lu-DOTA-CPN-PSMA;
FIG. 3 shows the injection of tumor-bearing nude mice 177 SPECT-CT imaging images after 1h, 4h, 24h and 72h after Lu-DOTA-CPN-PSMA;
FIG. 4 shows the injection of tumor-bearing nude mice 177 Lu-PSMA-I&SPECT-CT images 1h, 4h, 24h and 72h after T.
Detailed Description
For the purpose of making the objects, technical solutions and advantages of the present invention more apparent, the technical solutions in the present invention will be clearly and completely described below, and it is apparent that the described embodiments are some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
Example 1: preparation of inhibitor DOTA-CPN-PSMA (I-1)
In the first step, the reactor was charged with CTC resin (o-chlorophenyl-diphenyl-chloromethane, 1g,0.4 mmol), compound 1 (0.4 mmol,0.26 g), DIPEA (N, N-diisopropylethylamine, 1mmol,0.14 mL) and DMF (dimethylformamide, 8 mL). After the mixture was aerated for 3 hours, it was washed 3 times with DMF and 3 times with methanol to give Compound 2 (1.16 g). The degree of substitution of the resin was calculated based on the weight of the resin (compound 2), and the reaction scale was recalculated to be about 0.25mmol, and the yield of this step was 62.5%.
In the second step, the resin from step 1 was added to the reactor and swollen again with DMF (8 mL/g resin, about 9.5 mL) for 2 hours. The Fmoc protecting group was removed by bubbling a 20% solution of piperidine/DMF for 30 minutes with three times the resin bed volume and washed 5 times with DMF. To the reactor was charged 2 times Fmoc-3- (3-quinoline) -L-alanine (0.220 g), 1.9 times HATU (2- (7-azabenzotriazol) -N, N, N ', N' -tetramethyluronium hexafluorophosphate, 0.180 g), 4 times N-methylmorpholine (0.110 mL) and 0.5 times resin bed volume DMF (about 3 mL), and a small amount of resin was taken for ninhydrin detection to show negative after 1 hour of bubbling. The reaction solution was filtered off and washed 3 times with three times the volume of DMF of the resin bed. The above steps of Fmoc removal and amino acid ligation were repeated and tranexamic acid, lys (Dde) and DOTA (tris tBu) (DOTA-tri-tert-butyl-succinimidyl ester) were attached to the resin to give compound 3.
And thirdly, adding a 2% hydrazine hydrate/DMF solution with the volume of three times of the resin bed into the compound 3, bubbling for 30 minutes, filtering the solution in the reactor, and washing the solution with DMF with the volume of three times of the resin bed for 5 times to obtain the compound 4.
In the fourth step, 2 times of p-methylbenzoic acid (0.089 g), 1.9 times of HATU (0.180 g), 4 times of N-methyl morpholine (0.110 mL) and 0.5 times of DMF (dimethyl formamide) with the volume of resin bed are added into a reactor, and the mixture is aerated for 1 hour, and a small amount of resin is taken for ninhydrin detection, so that the negative effect is shown. The reaction solution was filtered off, washed 3 times with DMF volume of three times the resin bed volume, and then washed 3 times with methyl tert-butyl ether followed by vacuum drying to give Compound 5 (1.4 g). The yield of step 2-4 was 100%.
In the fifth step, 95% trifluoroacetic acid/water solution (14 mL) was added to the resin (Compound 5), and the mixed solution was stirred for 3 hours at a reaction temperature of 25 ℃. The resin was filtered and tert-butyl methyl ether (112 mL) was added to the filtrate at-20deg.C. The suspension was centrifuged, the supernatant was removed, tert-butyl methyl ether was added, the mixture was stirred to precipitate, and the precipitate was centrifuged again, the supernatant was removed, and the mixture was placed in a constant temperature oven for 16 hours, and tert-butyl methyl ether was drained (crude product 305mg was obtained). Purification by HPLC and salt exchange followed by lyophilization with a lyophilizer gave Ac salt of DOTA-CPN-PSMA as a white lyophilized powder (80 mg, overall yield 24.0%).
The synthetic route of the specific steps is as follows:
examples 2-3: preparation of inhibitors DOTA-OPN-PSMA (I-2) and DOTA-IPN-PSMA (I-3)
The inhibitor of examples 2-3 has the structures shown in formulas I-2 and I-3, and the preparation method can refer to example 1, so as to obtain the following corresponding structures:
example 3: preparation of Lu-177 labeled complex
The inhibitor DOTA-CPN-PSMA prepared in example 1 was dissolved in deionized water, followed by the addition of acetic acid-sodium acetate buffer solution or the direct dissolution of the inhibitor in the buffer solution, and the addition of the stabilizer gentisic acid or vitamin C. Removing the radioactive solution 177 Lu is added into a reaction tube filled with the solution and heated for reaction for 5 to 30 minutes. After the reaction, the mixture was cooled, and diluted with physiological saline. The said product is obtained 177 Lu-labeled radioactive complex 177 Lu-DOTA-CPN-PSMA).
Example 4: HPLC analysis and identification
Method analysis was performed using an Agilent Advancebio peptide map column (4.6X105 cm,2.7 μm); 1mL of trifluoroacetic acid was added to 1000mL of ultrapure water as mobile phase A; 1mL of trifluoroacetic acid was added to 1000mL of acetonitrile as mobile phase B; the flow rate is 1.0mL/min; the column temperature is 30 ℃; the detection wavelength is 220nm; the sample injection amount is 10 mu L; gradient elution was performed as follows.
TABLE 1 elution gradient and mobile phase composition
Time (min) A(％) B(％)
0 90 10
2 90 10
12 25 75
15 25 75
20 90 10
Through detection, the chemical purity of the target ligand is 97.59%, the retention time of a main peak is 8.25 minutes, and the radiochemical purity of the prepared radioactive liquid medicine is more than 95%, and the highest radiochemical purity can be more than 99%. The retention time of the main radioactive peak was 8.15 minutes, 177 the HPLC spectrum of Lu-DOTA-CPN-PSMA is shown in FIG. 2. The HPLC pattern of DOTA-CPN-PSMA is shown in FIG. 1.
Implementation 5: measurement of lipid partition coefficient
The markers were added separately to EP tubes containing the same volumes of n-octanol and water (0.5 mL:0.5 mL) and after capping thoroughly shaking 5min, the layers were separated by centrifugation in a centrifuge for 5min at 2000rpm. The organic phase and the aqueous phase were each taken in 100uL in a put-free tube, their radioactivity counts were measured in a well gamma detector, respectively, and the lipid fraction was calculated from the ratio of the radioactivity counts of the organic phase and the aqueous phase. P= lgN O /N W (N O And N W Counts of organic and aqueous phase samples, respectively). Repeating the operation for 3 times, taking an average value, and calculating the lipid water distribution coefficient of the marker.
Calculated from the measured data 177 The lipid distribution coefficient of Lu-DOTA-CPN-PSMA is-2.02, and 177 Lu-PSMA-I&compared with the lipid water distribution coefficient of-3.15, the T has higher lipophilicity and accords with the expectations of structural design.
Example 6: biodistribution and SPECT/CT imaging of tumor-bearing nude mice
Tumor-bearing mice were imaged by SPECT/CT at various time points after tail vein injection. Respectively taking 25.9 to 29.6MBq 177 Lu-DOTA-CPN-PSMA and 177 Lu-PSMA-I&t is injected into a nude mouse with tumor by tail vein, then the animal anesthetized by isoflurane is fixed on an animal SPECT scanner in a prone mode, static image acquisition is carried out 1h, 4h, 24h and 72h after administration respectively, and the scanning time is 20 minutes. The imaging results are shown in fig. 3 and 4, from which it can be seen, 177 Lu-DOTA-CPN-PSMA is metabolized primarily by the kidneys, as compared to control drugs 177 Lu-PSMA-I&T， 177 Lu-DOTA-CPN-PSMA exhibits better pharmacokinetic profile with higher tumor uptake and lower renal uptake. After 72 hours of administration, there was still strong drug uptake and retention in tumor-bearing mice.
In summary, the targeted Prostate Specific Membrane Antigen (PSMA) inhibitor and the preparation method thereof provided by the invention have the following advantages: the preparation method of the radionuclide-labeled targeted Prostate Specific Membrane Antigen (PSMA) medicament is simple, and the purification is carried out without using a C18 column or an HPLC preparation column, so that the radiochemical purity can reach more than 95 percent, and can reach more than 99 percent at most. The labeling yield is high and can reach more than 85%. And the medicines in clinical third phase are currently being developed 177 Lu-PSMA-I&T is of a higher degree thanHigh lipophilicity, stronger tumor uptake and retention, lower kidney uptake, small side effect and less adverse reaction, and can remarkably improve the treatment and imaging effects of the targeted PSMA nuclide so as to meet clinical requirements.
Finally, it should be noted that: the above embodiments are only for illustrating the technical solution of the present invention, and are not limiting; although the invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: the technical scheme described in the foregoing embodiments can be modified or some technical features thereof can be replaced by equivalents; such modifications and substitutions do not depart from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims (10)

1. A compound or a pharmaceutically acceptable salt thereof, wherein the compound has the structure shown in formula (I):
wherein R is 1 Independently selected from one of hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy; the groups adopted by the substitution are halogen.
2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from halogen, C 1 -C 12 Alkyl or C of (2) 1 -C 12 Is preferably CH 3 、OCH 3 Or I.
3. A process for the preparation of a compound as claimed in claim 1 or 2, comprising the steps of:
s1, taking CTC resin as a starting material, adding a compound 1 with a structure shown in the following formula for reaction:
s2, removing Fmoc protecting groups of the compound 1, and then adding Fmoc-3- (3-quinoline) -L-alanine to remove Fmoc; then, the amidation reaction of tranexamic acid, lys (Dde) and DOTA (tris tBu) is carried out by the same method;
s3, removing Dde groups of the Lys (Dde), and adding phenylbutyric acid or para-position substituents thereof to carry out amidation reaction; and then removing the residual protecting groups and the CTC resin to obtain the prostate specific membrane antigen inhibitor.
4. A process for the preparation of a compound according to claim 3, wherein step S1 comprises: the CTC resin and the compound 1 are subjected to air blowing reaction under the action of a catalyst N, N-diisopropylethylamine, and then the resin is washed to obtain the CTC resin grafted with the compound 1;
preferably, the reaction solvent of step S1 is DMF, and the washing comprises: washing with DMF and methanol was performed sequentially.
5. The method for producing a compound according to claim 3 or 4, wherein step S2 comprises: removing Fmoc protecting groups of the compound 1 by blowing with a solution of piperidine/DMF, and then washing the CTC resin grafted with the compound 1 with DMF; then Fmoc-3- (3-quinoline) -L-alanine, 2- (7-aza-benzotriazol) -N, N, N ', N' -tetramethyl urea hexafluorophosphate, N-methyl morpholine and DMF are added for air blowing reaction; finally, the amidation reaction of tranexamic acid, lys (Dde) and DOTA (tris tBu) was performed in the same manner.
6. The method for producing a compound according to claim 3 or 4, wherein step S3 comprises: adding hydrazine hydrate/DMF solution to remove Dde groups of the Lys (Dde); then adding phenylbutyric acid or para-substituent thereof, 2- (7-aza-benzotriazol) -N, N, N ', N' -tetramethyl urea hexafluorophosphate, N-methyl morpholine and DMF, and washing resin by adopting DMF and methyl tertiary butyl ether in sequence after the air blowing reaction is completed; finally, adding trifluoroacetic acid/water solution, removing the CTC resin, filtering, and purifying the filtrate by adopting tert-butyl methyl ether to obtain the prostate specific membrane antigen inhibitor;
preferably, after the tert-butyl methyl ether is adopted for purification, the tert-butyl methyl ether is pumped out, and after HPLC purification and salt exchange, the freeze drying is carried out to obtain the white freeze-dried powder of the prostate specific membrane antigen inhibitor;
preferably, the para-substituent is p-methylbenzoic acid, p-methoxybenzene butyric acid or p-iodobenzene butyric acid.
7. A radiolabel, characterized by the structural formula shown in formula (ii):
wherein R is 1 Independently selected from one of hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, wherein the groups employed for the substitution are halogen; m is selected from 68 Ga、 177 Lu、 64 Cu、 225 Ac、 212 Pb、 67 Cu、 161 Tb、 47 Sc or 90 Y.
8. The radiolabel according to claim 7, wherein R 1 Selected from halogen, C 1 -C 12 Alkyl or C of (2) 1 -C 12 Is preferably CH 3 、OCH 3 Or I.
9. A method of preparing a radiolabel according to claim 7 or 8, comprising: adding the compound of claim 1 or 2 into acetic acid-sodium acetate buffer solution, adding radioactive solution containing M, and reacting for 5-30 min to obtain the radiolabel.
10. Use of a compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, or a radiolabel according to claim 7 or 8, in the manufacture of a medicament for the diagnosis or treatment of prostate cancer.
CN202310495837.7A 2023-05-05 2023-05-05 Targeted prostate specific membrane antigen inhibitor, radioactive marker, preparation method and application thereof Pending CN117700479A (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN118165073A (en) * 2024-05-14 2024-06-11 中国药科大学 FAP inhibitor and preparation method and application thereof

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN118165073A (en) * 2024-05-14 2024-06-11 中国药科大学 FAP inhibitor and preparation method and application thereof
CN118165073B (en) * 2024-05-14 2024-07-19 中国药科大学 FAP inhibitor and preparation method and application thereof

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